The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse and the consequences of that abuse. Studies have indicated that: (1) The psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, are mediated by both D1 and D2 dopamine receptors. For increase in learned operant behavior produced by cocaine, however, D2 receptors have a greater involvement than do D1 receptors. The respective roles of other dopamine receptors are currently under investigation. (2) There are differences among dopamine uptake inhibitors in the relationships of their behavioral effects and their affinity for the dopamine transporter. For drugs that have a structural similarity to cocaine there is a direct relation between affinity for the transporter and in vivo potency. In contrast, for structurally dissimilar compounds their is no simple relationship. These data indicate that cocaine and its congeners bind to the dopamine transporter in a manner that is distinct from that of other dopamine uptake inhibitors. (3) The subjective behavioral effects of cocaine are mediated by both D1 and D2 dopamine receptor systems, although actions through either system alone are not sufficient to fully reproduce the subjective effects of cocaine. (4) The subjective behavioral effects of low doses of cocaine are mediated by both D1 and D2 dopamine receptor systems, although actions through the D1 dopamine system appear to predominate. In addition, the subjective effects of low doses of cocaine have a significant noradrenergic component that is not evident in the effects of higher doses of cocaine. (5) Anhydroecgonine methyl ester (AEME) is a major pyrolysis product of cocaine and has been detected in high concentration in the urine of subjects who have smoked "crack." In addition, AEME has a structural resemblance to anatoxin-A, a known cholinergic toxin. The contribution of AEME to the unique pharmacological actions of "crack" was investigated. These studies found that AEME probably does not contribute in a significant way to the stimulant or subjective effects of "crack" or its toxicity. (6) Tolerance to the behavioral effects of cocaine is not accompanied by changes in the function of dopamine D1 receptors. Further studies are being conducted to assess the effects of cocaine treatment on functional aspects of other dopamine receptor subtypes. (7) Unique compounds have been synthesized that have high affinity for the dopamine transporter and inhibit dopamine uptake. However, these drugs do not have behavioral effects that are similar to those of cocaine. Initial structure-activity studies indicate that the binding of these compounds to the dopamine transporter is different from that for cocaine. Because these compounds bind to the dopamine transporter but do not have cocaine-like behavioral effects, they may serve as cocaine antagonists, which is currently under investigation.